Insomnia affects 25-30% of older Americans. In fact, the timing and structure of sleep exhibit marked changes with aging, including earlier bed and wake times, impaired sleep consolidation and a reduction in slow-wave sleep. These even occur in healthy older people, indicating that they are a primary neurobiological consequence of the aging process rather than secondary to other ailments. We propose to investigate age- related neurobiological changes in sleep-wake regulation. The alternation between sleep and wakefulness is regulated by the interaction of two neuro-anatomically and functionally distinct neurobiological processes: circadian rhythmicity and sleep homeostasis. Data collected in the previous grant period have demonstrated conclusively that the timing of sleep and wakefulness can only be understood by considering the interaction between both processes. Assessment of the mechanisms underlying such interaction requires investigation at a number of levels: clinical, behavioral, neurophysiologic, cellular and molecular. The multi-disciplinary approach we developed during the previous grant period has been expanded in the proposed studies to take advantage of the remarkable scientific progress that has taken place over the past 7 years in the identification of variations in gene transcription/translation, neuro- modulators and hormones associated with both the circadian and the sleep homeostatic process, as well as identification of a putative neuro- anatomical location where interaction between the circadian and homeostatic processes may occur. To achieve the goal of understanding the role of the circadian and homeostatic sleep processes in age-related changes in sleep timing and consolidation, the proposed program will investigate such changes in sleep and/or circadian biology at the behavioral and electrophysiologic level as well as the neuro-anatomical and molecular level, and will further test a therapeutic intervention in a double-blind placebo controlled clinical trial of the efficacy of exogenous melatonin as a hypnotic in healthy older people. This research has important implications for the development of rational therapies for age-related insomnia, based on the patho-physiology of sleep disruption in older people.